1. Field of the Invention
The present invention provides prokinetic agents with superior pharmacological and pharmacokinetic properties for the treatment of gastrointestinal motility disorders. The invention relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology, and pharmacology.
2. Description of Related Art
Gastrointestinal (“GI”) motility regulates the orderly movement of ingested material through the gut to insure adequate absorption of nutrients, electrolytes and fluids. Appropriate transit through the esophagus, stomach, small intestine and colon depends on regional control of intraluminal pressure and several sphincters that regulate forward movement and prevent back-flow of GI contents. The normal GI motility pattern may be impaired by a variety of circumstances including disease and surgery.
Disorders of gastrointestinal motility include, for example, gastroparesis and gastroesophageal reflux disease (“GERD”). Gastroparesis is the delayed emptying of stomach contents. Symptoms of gastroparesis include stomach upset, heartburn, nausea, and vomiting. Acute gastroparesis may be caused by, for example, drugs (e.g., opiates), viral enteritis, and hyperglycemia, and is usually managed by treating the underlying disease rather than the motility disorder. The most common causes of chronic gastroparesis are associated with long standing diabetes or idiopathic pseudo-obstruction, often with so-called “non-ulcer” or “functional” dyspepsia.
GERD refers to the varied clinical manifestations of reflux of stomach and duodenal contents into the esophagus. The most common symptoms are heartburn and dysphasia; blood loss may also occur from esophageal erosion. GERD may be associated with low tone and inappropriate relaxation of the lower esophageal sphincter and occurs with gastroparesis in about 40% of cases. In most cases, GERD appears to be treatable with agents that reduce the release of acidic irritant by the stomach (e.g., Prilosec) or agents that increase the tone of the lower esophageal sphincter (e.g., cisapride). Other examples of disorders whose symptoms include impaired gastrointestinal motility are anorexia, gall bladder stasis, postoperative paralytic ileus, scleroderma, intestinal pseudoobstruction, gastritis, emesis, and chronic constipation (colonic inertia).
These GI disorders are generally treated with prokinetic agents that enhance propulsive motility. Motilides are macrolide compounds such as erythromycin and its derivatives that are agonists of the motilin receptor. Evidence of the potential clinical utility of motilides includes their ability to induce phase III of Migrating Motor Complexes (“MMC”). MMC refers to the four phases (I-IV) of electrical activity displayed by the stomach and small intestine in the fasting state. Muscular contraction occurs in phases III and IV, coincident with a peristaltic wave that propels enteric contents distally during fasting. Other clinically relevant effects include: increase in esophageal peristalsis and LES pressure in normal volunteers and patients with GERD; acceleration of gastric emptying in patients with gastric paresis; and stimulation of gallbladder contractions in normal volunteers, patients after gallstone removal, and diabetics with autonomic neuropathy.
The erythromycins are a family of macrolide antibiotics made by the fermentation of the Actinomycetes Saccharopolyspora erythraea (formerly Streptomyces erythreus). Erythromycin A, a commonly used antibiotic, is the most abundant and important member of the family.
Erythromycin ARa = OHRb = MeErythromycin BRa = HRb = MeErythromycin CRa = OHRb = HErythromycin DRa = HRb = H
Since the 1950's, erythromycin A (1) has been known to cause GI side effects such as nausea, vomiting, and abdominal discomfort. Erythromycin A undergoes acid catalyzed degradation in the stomach, forming initially 8,9-anhydro-6,9-hemiacetal 2 (also known as erythromycin A enol ether) and then spiroketal 3, as shown in Scheme A. The GI side effects are largely explained by motilin agonist activity in erythromycin A itself and hemiacetal 2. (Spiroketal 3 is inactive.) 
Omura et al., “Gastrointestinal motor-stimulating activity of macrolide antibiotics and the structure-activity relationship,” J. Antibiotics (1985) 38: 1631-2, discloses the relative ability of erythromycin A, 9-dihydroerythromycin A, and other macrolides to stimulate gut contraction in conscious dogs. In this assay, 9-dihydroerythromycin A was reported to be 65% as active as erythromycin at a dose of 1 mg/kg. As 9-dihydroerythromycin cannot form an enol ether, it is clear that enol ether formation is not essential for motilide activity. Erythromycin A is currently used to treat motility disorders, even though its antibacterial activity raises concerns over generation of resistant microorganisms. As 9-dihydroerythromycin also shows antibacterial activity, there are similar concerns with its use as a motilide.
A number of erythromycin enol ether analogs have been prepared as motilides, including EM-523 (4); EM-574 (5); LY267,108 (6); GM-611 (7); and ABT-229 (8) whose structures are shown below. See U.S. Pat. Nos. 5,578,579; 5,658,888; 5,922,849; 6,077,943; and 6,084,079; each of which is incorporated herein by reference. 
Other motilides of interest include lactam enol ethers and lactam epoxide derivatives. See U.S. Pat. Nos. 5,712,253; 5,523,401; 5,523,418; 5,538,961; and 5,554,605; each of which is incorporated herein by reference.
Despite the high potency of the erythromycin enol ethers as motilides, their metabolic instability has hindered their development in the clinic. Further, compounds such as 7 and 8 show motilin receptor desensitization in both cell-based and muscle strip contractility assays. This desensitization may portend a decrease in efficacy upon multiple dosing of the motilide.
There thus exists a need for new motilide compounds having decreased antibacterial activity, increased metabolic stability, and decreased receptor desensitization. The present invention provides analogs of 9-dihydroerythromycin that meet this need.